Abstract Obesity is the second leading cause of preventable deaths in the United States. Weight loss, and maintenance of weight loss, improves cardiovascular disease risk factors, physical functioning, and quality of life. Interventions that combine dietary change, physical activity increase, and behavioral strategies are efficacious for short-term weight loss but less so for long-term weight loss. Given that the best predictor of long-term weight loss is initial weight loss, strategies are needed to enhance both initial weight loss and weight loss maintenance. Dietary and physical activity behaviors often are influenced by domestic partners. Therefore, intervening jointly on patients and their partners is likely to improve the efficacy of weight management programs. This study involves an evaluation of the role of domestic partner support in a comprehensive weight loss initiation and maintenance program. Eligibility criteria include age 18-75, BMI ?27 kg/m2 with an obesity- related comorbidity or BMI ?30 kg/m2, and cohabitating with a domestic partner. 230 couples will be randomized to 18-month comprehensive weight program directed at patients alone or involving their partners. In months 1-6, all patients will receive group-based weight loss program featuring a calorie-restricted diet and physical activity. In months 7-18, all patients will receive a weight loss maintenance intervention that involves maintenance-specific content, transitions to individual telephone calls, and gradually decreases in frequency of contact. In the partner-assisted arm, partners will learn and practice communication skills and support strategies to facilitate patient health behavior change. Partners will attend patient group sessions, be informed of patients' goals (during initiation) and relapse plans (during maintenance), and receive reinforcing text messages. In months 19-24, intervention will be withdrawn to examine sustainability of effects. Our primary hypothesis is that average 24-month weight in the partner-assisted intervention will be at least 2.5 kg lower than in the patient-only intervention. Secondary outcomes include caloric intake and physical activity at 24 months. Mediation analyses will examine the role of interdependence theory constructs and social support. If successful, this approach could inform refinement and implementation of effective obesity treatments.